Project Summary/Abstract Men who have sex with men (MSM) are the population most affected by HIV in the United States, accounting for over two-thirds of all new HIV diagnoses. Pre-exposure prophylaxis (PrEP) has demonstrated high levels of efficacy for HIV prevention, however, PrEP initiations have been low nationwide, and discontinuation rates are high. On-demand PrEP, or the use of oral PrEP before/after sex, has been shown to be highly effective in clinical trials and real-world practice and has been endorsed by the International Antiviral Society-USA and World Health Organization. MSM in the US not interested in taking a daily pill have expressed high levels interest in on-demand PrEP, and several clinics have begun offering on-demand PrEP as an alternative to daily PrEP. However, there are substantial concerns about adherence to this complex regimen (2 pills 2-24 hours before sex, 1 pill 24 and 48 hours later). Tools to support individuals who choose to use on-demand PrEP are critical to ensure effectiveness and minimize harm of on-demand dosing. In this R34 application, we propose to develop and refine a mobile app, PrEPmate 211, to support the safe and effective use of on- demand PrEP among US MSM. Grounded in the situated Information, Motivation, Behavioral Skills model, this app will feature 1) PrEP 211 Basics providing information on how to take on-demand PrEP; 2) motivational weekly check-in messages to provide support; 3) a sexual and pill-taking diary, with reminders for pre/post-sex doses and display showing time to protection; and 4) a shared decision-making tool on whether to continue on- demand PrEP or switch to daily PrEP. In aim 1, we will assess patient and provider-identified barriers and facilitators of on-demand PrEP use through focus groups with 20 MSM and interviews with 5-7 clinical providers, and elicit their feedback to inform the development of PrEPmate 211. In aim 2, we will conduct a 2 month optimization pilot among 12-15 MSM taking on-demand PrEP to refine the functionality, technical performance, and user satisfaction of the app. In aim 3, we will conduct a pilot randomized controlled trial to evaluate the feasibility, acceptability, and preliminary impact of PrEPmate 211 to increase PrEP coverage of sex acts. In this trial, we will enroll 60 MSM currently taking or interested in starting on-demand PrEP who will be randomized 2:1 to receive PrEPmate 211 (N=40) or enhanced standard of care (brochure and counseling on on-demand PrEP with bottle timer cap showing time of last dose, N=20). Feasibility and acceptability of the app will be assessed through app paradata of usage patterns and the System Usability Scale. Preliminary impact will be assessed by evaluating the proportion of sex acts covered by PrEP assessed via sex/dosing data entered into PrEPmate 211 or a web app; we will also pilot the use of a novel urine tenofovir self-test strip to confirm PrEP dosing in the past week. Upon project completion, we will have developed a highly innovative tool to support MSM using on-demand PrEP ready for testing in a larger efficacy trial.